Mirtazapine Solid Dosage Forms

ABSTRACT

A non-effervescent, solid dosage form containing mirtazapine, which is used to form mirtazapine pharmaceutical tablets. The dosage form contains mirtazapine, a hydrophilic component, and at least one lubricant. In some embodiments, the dosage forms contain a salivating agent. Processes for producing mirtazapine orally disintegrating tablets are also provided.

The application claims the benefit of U.S. Provisional Application No.60/491,279, filed Jul. 31, 2003, which is herein incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is generally related to solid dosage forms ofmirtazapine for the treatment of depression and other neurologicaldisorders and diseases.

2. Related Art

Mirtazapine is the common name of the isomeric compound1,2,3,4,10,14β-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine.The use of mirtazapine is well known for the treatment of depression andthe symptoms associated with depression including, memory loss, changesin mood, insomnia, lethargy, increase or decrease in weight, andanxiety.

Mirtazapine treats depression by antagonizing the adrenergic 5-HT2A,5-HT3, and alpha 2 autoreceptors and alpha 2-heteroreceptors, andenhancing the release of norepinephrine and 5-HT1A-mediated serotonergictransmission. It is not known exactly how mirtazapine accomplishes thisfunction. It is also being considered for the treatment of psychoticdisorders and diseases such as schizophrenia and movement disorders suchas Parkinson's tremors, as disclosed in U.S. Pat. No. 6,281,207.Mirtazapine can be administered alone or with other pharmaceuticals suchas selective serotonin reuptake inhibitors (SSRIs), such as thosedescribed in U.S. Pat. No. 5,977,099, or antipsychotic agents, such asthose described in U.S. Pat. No. 6,150,353.

Mirtazapine has been found to have limited drug interaction and few sideeffects associated with many antidepressants such as sexual dysfunction.The tetracylic compound is currently manufactured through the methodsdescribed in U.S. Pat. No. 4,062,848, forming a racemic mixture ofisomeric compounds.

Oral administration in the form of a conventional tablet, pill orcapsule constitutes the generally preferred route for administration ofpharmaceuticals, such as mirtazapine, since this route is generallyconvenient and acceptable to patients. Unfortunately such compositionsmay be associated with certain disadvantages, particularly in thetreatment of pediatric or geriatric patients, who may dislike or havedifficulty in swallowing such compositions, or where administration of aconventional tablet, pill or capsule is not feasible. It is highlydesirable, particularly in the treatment of acute conditions, thatpharmaceutical compositions have a rapid and consistent onset of actioncombined with sustained activity and good bioavailability.

Since a solid preparation such as an oral tablet requires water forswallowing, a liquid dosage form is normally preferred for the elderly,infants or patients who have difficulty in swallowing. However, a liquidpreparation has shortcomings regarding difficulties in handling,especially in measuring an accurate dosage, and that it is not suitablefor drugs which are unstable in a moist environment. Thus, an effort hasbeen made to develop a rapidly disintegrating tablet of drugs which caneasily disintegrate by the action of saliva.

For example, oral dosage forms have been developed includingeffervescents which rapidly disintegrate in the mouth and providetaste-masking. See Wehling et al., U.S. Pat. No. 5,178,878. These dosageforms provide significant problems in terms of production, storage,transport and during consumer usage. They are also significantly morecostly to produce than conventional tablets.

U.S. Pat. No. 5,178,878 discloses an effervescent tablet which comprisesmicroparticles of various active ingredients. Effervescence is typicallycreated by the formation of gas bubbles upon a reaction of an alkalimetal carbonate or carbonate source with an acid or an acid source. Theeffervescence aids in the complete disintegration of the tablet uponoral administration.

Mirtazapine is currently available in an effervescent oraldisintegrating tablet. However, effervescent tablets containing analkalizing agent are usually moisture sensitive, may be incompatiblewith an acidic drug and require protection due to their sensitivity tohumidity. In addition, the manufacture of effervescent tablets requiresstrict humidity controls.

Therefore, there is a need for an orally disintegrating tablet of apharmaceutical composition that does not require an alkalizing agentsuch as a carbonate or bicarbonate; is compatible with an acidic drug;is physically stable under humid conditions; and is easier tomanufacture.

SUMMARY OF THE INVENTION

In some embodiments, the invention provides a non-effervescent, soliddosage form adapted for oral administration to a mammal:

about 1 to about 60% by weight of mirtazapine;

about 1 to about 95% by weight of a hydrophilic component selected fromthe group consisting of a water-soluble component, a water-insolublecomponent, or combinations thereof, wherein the water-soluble componentis selected from the group consisting of cellulose derivatives, polyol,water-soluble carbohydrate, a component having a —CHOH group,hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, a component having a —CHCOOH group,tartaric acid, citric acid, malic acid, succinic acid, sodium andpotassium salts thereof, or combinations thereof, wherein thewater-soluble carbohydrate is selected from the group consisting ofmannitol, xylitol, sorbitol, malitol, lacitol, erytritol, xylose,arabinose, pentose, galactose, dextrose, inositol, sucrose, trehalose,or combinations thereof, and wherein the water-insoluble component isselected from the group consisting of microcrystalline cellulose,crospovidone, croscarmelose sodium, sodium starch glycolate, AMBERLITE(Rohm and Haas, Philadelphia, Pa.), calcium silicate, calciumtrisilicate, magnesium silicate, magnesium trisilicate, modifiedstarches, or combinations thereof;

up to about 5% by weight of at least one lubricant selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, talc, hydrogenated vegetableoil, aluminum stearate, silica gel, colloidal silicon dioxide, orcombinations thereof;

wherein said dosage form does not rely upon effervescence fordisintegration of said dosage form;

wherein dissolution of said dosage form in a medium of 900 mL of 0.1 NHCl with a paddle speed of 50 rpm is greater than about 75% at fiveminutes; and

wherein the water-soluble and water-insoluble component are provided ina weight ratio from about 20:80 to about 95:5.

In some embodiments, the solid dosage form further comprises about 0.1to about 30% by weight of at least one salivating agent selected fromthe group consisting of mannitol, xylitol, tartaric acid, citric acid,malic acid, fumaric acid, adipic acid, succinic acid, sodium andpotassium salts thereof, and combinations thereof.

In some embodiments, the dosage form further comprises, about 1 to about50% of a first hydrophilic component selected from a group consisting ofcellulose derivatives, hydrophilic polymers, polyvinyl pyrrolidone, andcombinations thereof. In some embodiments, the first hydrophiliccomponent is selected from the group consisting of microcrystallinecellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and combinations thereof.

In some embodiments the dosage form comprises a component having anegative heat of solution, the component selected from the groupconsisting of mannitol, xylitol, sorbitol, sucrose, and combinationsthereof.

The solid dosage forms of the present invention do not rely uponeffervescence for release of the active agent since the present dosageforms lack the base necessary for the effervescent-causing reaction,i.e. the release of bicarbonate. In some embodiments, the solid dosageforms of the present invention have a have a dissolution of greater than75% in five mins in a medium of 900 mL of 0.1 N HCl with a paddle speedof 50 rpm. In some embodiments, the solid dosage forms of the presentinvention have a have a dissolution of greater than 95% in five mins ina medium of 900 mL of 0.01 N HCl with a paddle speed of 50 rpm.

In some embodiments, the invention provides a process of making anon-effervescent, solid dosage form adapted for oral administrationwhich comprises:

a) mixing about 1 to about 60% by weight of mirtazapine;

about 1 to about 95% by weight of a hydrophilic component selected fromthe group consisting of a water-soluble component, a water-insolublecomponent, or combinations thereof, wherein the water-soluble componentis selected from the group consisting of cellulose derivatives, polyol,a component having a —CHOH group, water-soluble carbohydrate,hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, a component having a —CHCOOH group,tartaric acid, citric acid, malic acid, succinic acid, sodium andpotassium salts thereof, and combinations thereof, wherein thewater-soluble carbohydrate is selected from the group consisting ofmannitol, xylitol, sorbitol, malitol, lacitol, erytritol, xylose,arabinose, pentose, galactose, dextrose, inositol, sucrose, trehalose,and combinations thereof, and wherein the water-insoluble component isselected from the group consisting of microcrystalline cellulose,crospovidone, croscarmelose sodium, sodium starch glycolate, AMBERLITE,calcium silicate, calcium trisilicate, magnesium silicate, magnesiumtrisilicate, modified starches, and combinations thereof; and

up to about 5% by weight of at least one lubricant selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, talc, hydrogenated vegetableoil, aluminum stearate, silica gel, colloidal silicon dioxide, andcombinations thereof in an agitator to form a mixture;

b) followed by directly compressing the mixture to form a pharmaceuticaltablet,

wherein said tablet does not rely upon effervescence for disintegrationof said tablet, wherein dissolution of said dosage form in a medium of900 mL of 0.1 N HCl with a paddle speed of 50 rpm is greater than about75% at five minutes, and wherein the water-soluble and water-insolublecomponent are provided in a weight ratio from about 20:80 to about 95:5.

In some embodiments, the process further comprises mixing, about 1 toabout 50% of a first hydrophilic component selected from a groupconsisting of cellulose derivatives, hydrophilic polymers, polyvinylpyrrolidone, and combinations thereof. In some embodiments, the firsthydrophilic component is selected from the group consisting ofmicrocrystalline cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and combinationsthereof.

Pharmaceutical tablets formed from this process are also provided by thepresent invention. The solid dosage forms of the present invention donot rely upon effervescence for release of the active agent since thepresent dosage forms lack the base necessary for theeffervescent-causing reaction, i.e. the release of bicarbonate. In someembodiments, the solid dosage forms of the present invention have a havea dissolution of greater than 75% in five mins in a medium of 900 mL of0.1 N HCl with a paddle speed of 50 rpm. In some embodiments, the soliddosage forms of the present invention have a have a dissolution ofgreater than 95% in five mins in a medium of 900 mL of 0.01 N HCl with apaddle speed of 50 rpm.

In some embodiments, the invention provides a method of treatingneurological disorders and diseases including depression, symptomsassociated with depression including suicidal thoughts, drowsiness,memory loss, anxiety, sleeplessness and others, psychotic disorders anddiseases such as schizophrenia and movement disorders and diseases in ahuman which comprises administering the solid dosage form of the presentinvention to a mammal in need thereof.

Particularly, the present invention provides for mirtazapine orallydisintegrating tablets which do not rely upon effervescence for releaseof the active agent. The non-effervescent, mirtazapine tablets havevarious advantages over effervescent tablets. For example, the presentdosage form does not require an alkalizing agent such as a carbonate orbicarbonate; a non-effervescent, tablet is compatible with an acidicdrug; the present pharmaceutical tablet is more physically stable, lesssensitive to humidity, and thus are easier to package since they neednot be protected from moisture at all times; and the manufacture of thepresent pharmaceutical tablets does not require the strict humiditycontrols that effervescent tablets typically do.

In some embodiments, the hardness of the non-effervescent, solid dosageforms is about 0.1 to about 5 kp. In some embodiments, the hardness ofthe dosage forms is about 0.1 to about 3 kp. In some embodiments, thehardness of the dosage forms is greater than about 1.0 kp after exposurefor 24 hours at 25° C. and 60% relative humidity, and is greater thanabout 0.8 kp after exposure for 60 minutes at 40° C. and 75% relativehumidity.

In some embodiments the invention provides a non-effervescent, soliddosage form, wherein the dosage form having a first hardness being thedosage form inside a closed space, wherein the dosage form having asecond hardness being the dosage form exposed to about 25° C. and about60% relative humidity for about 24 hours, and wherein the secondhardness is at least about 50% of the first hardness. In someembodiments, the invention provides, a non-effervescent, solid dosageform, wherein the dosage form having a first hardness being the dosageform inside a closed space, wherein the dosage form having a secondhardness being the dosage form exposed to about 40° C. and about 75%relative humidity for about 15 minutes, and wherein the second hardnessis at least about 50% of the first hardness.

Thus, an orally disintegrating tablet of a mirtazapine pharmaceuticalcomposition is provided which does not require an alkalizing agent suchas a carbonate or bicarbonate; is compatible with an acidic drug; isphysically stable under humid conditions; and is easier to manufacture.The mirtazapine dosage form of the present invention provides orallydisintegrating tablets having a high tolerance of humidity; maintaintheir physical integrity when exposed to environmental conditions thusfacilitating processing, compressing and packaging; are more stableunder harsh conditions; and last longer when removed from packaging ascompared to reference mirtazapine tablets.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a flow chart illustrating a dry-mixing process of making someof the mirtazapine formulations according to the present invention.

FIG. 2 is a dry-mixing process of making some of the mirtazapineformulations of the present invention.

FIG. 3 is a graph showing the effect of temperature and humidity on the15 mg mirtazapine orally disintegrating tablets provided in Table 8.

FIG. 4 is a graph showing the effect of temperature and humidity on the30 mg mirtazapine orally disintegrating tablets provided in Table 8.

FIG. 5 is a graph showing the effect of temperature and humidity on the45 mg mirtazapine orally disintegrating tablets provided in Table 8.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the present document, all expressions of percentage, ratio,and the like, will be in weight units unless otherwise indicated.

The present invention contemplates solid oral dosage forms, such as apharmaceutical tablet containing mirtazapine. The dosage forms of thepresent invention do not rely upon effervescence for release of theactive agent. The mirtazapine formulations contemplated can employ aracemic mixture of mirtazapine or an enantiomeric excess of, or asubstantially pure enantiomer, i.e., R-mirtazapine and S-mirtazapine.See U.S. Pat. No. 4,062,848. As will be appreciated by those skilled inthe art, salts, hydrates, solvates, and the like, could be employed inthe present invention to obtain the same beneficial effects as thatprovided by the base form mirtazapine. Accordingly, as used herein, theterm “mirtazapine” contemplates all such forms, with a racemic mixtureof mirtazapine being preferred.

As used herein, the term “pharmaceutically effective” refers to thatamount of mirtazapine, which diminishes one or more symptoms of thedisease or disorder being treated. For example, a pharmaceuticallyeffective amount for the treatment of depression refers to the amountwhich when administered diminishes one or more symptoms of depression,such as insomnia or anxiety. The precise therapeutic dosage ofmirtazapine necessary to be pharmaceutically active will vary with age,size, sex and condition of the subject, the nature and severity of thedisorder or disease to be treated, and the like; thus, a precisepharmaceutically effective amount cannot be specified in advance andwill be determined by a caregiver. However, appropriate amounts can bedetermined by routine experimentation with animal models. In generalterms, an effective daily dose is about 5 to 50 milligrams (mg) per dayper human subject of mirtazapine. In some embodiments, an effectivedaily dose is about 5 mg per day. In some embodiments, an effectivedaily dose is about 10 mg per day. In some embodiments, an effectivedaily dose is about 15 mg per day. In some embodiments, an effectivedaily dose is about 30 mg per day. In some embodiments, an effectivedaily dose is about 45 mg per day.

The term “tablet” as used herein is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes, whethercoated or uncoated.

As used herein, the term “excipient” refers to the additives used toconvert an active compound into a form suitable for its intendedpurpose. For dosage forms of the present invention suitable foradministration to humans, the term “excipient” is meant to include, butis not limited to, those ingredients described in Remington: The Scienceand Practice of Pharmacy, Lippincott Williams & Wilkins, 21^(st) ed.(2004), which is herein incorporated by reference in its entirety.

As used herein, the term “disintegration” refers to the loss ofintegrity of the dosage forms of the invention to form granules oraggregates or particles, as generally described in Remington: TheScience and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^(st)ed. (2004).

As used herein, “dissolution” refers to the process by which mirtazapinegoes into solution from the solid dosage forms of the invention.

As used herein, a “closed space” refers to the space within a package orcontainer such as a blister pack or foil-wrapped package containing thesolid dosage forms of the invention.

As used herein, “low humidity” refers to the conditions provided by useof desiccated bags to control moisture or to conditions inside a packagesuch as a blister pack containing the solid dosage forms of theinvention.

In some embodiments, the invention provides a non-effervescent, soliddosage form adapted for oral administration to a mammal:

about 1 to about 60% by weight of mirtazapine;

about 1 to about 95% by weight of a hydrophilic component selected fromthe group consisting of a water-soluble component, a water-insolublecomponent, or combinations thereof, wherein the water-soluble componentis selected from the group consisting of cellulose derivatives, polyol,water-soluble carbohydrate, a component having a —CHOH group,hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, a component having a —CHCOOH group,tartaric acid, citric acid, malic acid, succinic acid, sodium andpotassium salts thereof, or combinations thereof, wherein thewater-soluble carbohydrate is selected from the group consisting ofmannitol, xylitol, sorbitol, malitol, lacitol, erytritol, xylose,arabinose, pentose, galactose, dextrose, inositol, sucrose, trehalose,or combinations thereof, and wherein the water-insoluble component isselected from the group consisting of microcrystalline cellulose,crospovidone, croscarmelose sodium, sodium starch glycolate, AMBERLITE(Rohm and Haas, Philadelphia, Pa.), calcium silicate, calciumtrisilicate, magnesium silicate, magnesium trisilicate, modifiedstarches, or combinations thereof;

up to about 5% by weight of at least one lubricant selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, talc, hydrogenated vegetableoil, aluminum stearate, silica gel, colloidal silicon dioxide, orcombinations thereof;

wherein said dosage form does not rely upon effervescence fordisintegration of said dosage form;

wherein dissolution of said dosage form in a medium of 900 mL of 0.1 NHCl with a paddle speed of 50 rpm is greater than about 75% at fiveminutes; and

wherein the water-soluble and water-insoluble component are provided ina weight ratio from about 20:80 to about 95:5. In some embodiments, thedissolution of the dosage form in a medium of 900 mL of 0.01 N HCl witha paddle speed of 50 rpm is greater than about 95% at five minutes.

In some embodiments, the dosage form further comprises about 0.1 toabout 30% by weight of at least one salivating agent selected frommannitol, tartaric acid, citric acid, malic acid, fumaric acid, adipicacid, succinic acid, sodium and potassium salts thereof, andcombinations thereof.

In some embodiments, the dosage form further comprises, about 1 to about50% of a first hydrophilic component selected from a group consisting ofcellulose derivatives, hydrophilic polymers, polyvinyl pyrrolidone, andcombinations thereof. In some embodiments, the first hydrophiliccomponent is selected from the group consisting of microcrystallinecellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and combinations thereof.

The dosage forms of the present invention do not rely upon effervescencefor release of the active agent, need not contain an alkalyzing agent,but can contain any other additives, colorings and/or flavorings thatare pharmaceutically acceptable. In some embodiments, the dissolutionrate of dosage forms of the present invention, in a medium of 900 mL of0.01 N HCl with a paddle speed of 50 rpm, is greater than 95% at fiveminutes.

In some embodiments, the dosage form comprises about 0.5 to about 40%mirtazapine, up to about 30% of at least one salivating agent, about 5to about 50% of a first hydrophilic component, about 10 to about 80% ofa water-soluble carbohydrate, about 10 to about 50% of a disintegratingagent, and less than about 5% of at least one lubricant.

In some embodiments, the dosage form comprises about 0.5 to about 10% byweight of mirtazapine; up to about 10% by weight of at least onesalivating agent; about 5 to about 15% by weight of a first hydrophiliccomponent; about 35 to about 65% by weight of a water-solublecarbohydrate; about 15 to about 35% by weight of a disintegrating agent;and about 0.5 to about 4% by weight of at least one lubricant.

In some embodiments, the dosage form comprises about 6% mirtazapine,about 14.4% of one or more salivating agents, about 6% of a firsthydrophilic component, about 44% of a water-soluble carbohydrate, about24% of a disintegrating agent, and about 1.4% of at least twolubricants.

The present invention contemplates the use of at least one salivatingagent source suitable for human consumption. Salivating agents includeorganic compounds such as polyols and mild acids. Examples ofwater-soluble carbohydrates and polyols which can be used as salivatingagents in the present invention are xylitol and mannitol. Mild acids areused to adjust the pH, or acidity, of the pharmaceutical composition andin some cases to provide flavoring. A purpose of using a mild acid inthe present composition is to provide for a sour taste to stimulatesaliva secretion, which helps disintegrate the tablets. Acceptable mildacids are tartaric acid, citric acid, malic acid, fumaric acid, adipicacid, succinic acid, sodium and potassium salts thereof, andcombinations thereof. Also contemplated is the use of acid anhydridesand acid salts such as sodium dihydrogen phosphate, disodium dihydrogenpyrophosphate, acid citrate salts, and sodium acid sulfite. It ispreferred that either tartaric acid, citric acid, or both, or sodium orpotassium salts thereof, or combinations thereof are used in the presentformulation. Most preferred is a combination of tartaric acid, NF andcitric acid USP Anhydrous Powder.

Preferred water-soluble carbohydrates for use in the present inventioninclude but are not limited to mannitol, xylitol, sorbitol, malitol,lacitol, erytritol, xylose, arabinose, pentose, galactose, dextrose,inositol, sucrose, trehalose and mixtures thereof, most preferably,mannitol USP available under the trade name PARTECK M-200 (Merck KGaA,Darmstadt, Germany).

In some embodiments, the invention provides a solid dosage form whichfurther comprises a component having a negative heat of solutionselected from the group consisting of mannitol, xylitol, sorbitol,sucrose, and combinations thereof.

The mirtazapine dosage form of the present invention neither relies uponeffervescence for release of the active agent nor aids in its completedisintegration. Instead, the present invention employs a disintegratingagent. Particularly useful disintegrating agents aresuper-disintegrating agents such as crospovidone, croscarmelose sodium,AMBERLITE (Rohm and Haas, Philadelphia, Pa.), and sodium starchglycolate. The preferred disintegrating agent is crospovidone, NFavailable under the trade name POLYPLASDONE XL (ISP Technologies, Wayne,N.J.). Microcrystalline cellulose also aids in disintegration by actingas a wicking agent. Wicking agents take moisture from the ambientconditions and draws it into the tablet to aid in dissolving the watersoluble components. Types of AMBERLITE (Rohm and Haas, Philadelphia,Pa.) resins for use in the formulation include but are not limited toAMBERLITE IRP64, AMBERLITE IRP69, AMBERLITE IRP88, and combinationsthereof The components of the present invention are sufficient forcomplete disintegration without the use of effervescent agents. In someembodiments, the dosage form further comprises an agent selected fromthe group consisting of calcium silicate, magnesium silicate, magnesiumtrisilicate, and combinations thereof. While not wishing to be bound bya specific theory, it appears that the agent, such as, calcium silicate,calcium trisilicate, magnesium trisilicate, magnesium silicate, andcombinations thereof, might act by facilitating the disintegrationaction of the disintegrating agents such as crospovidone. In someembodiments, the weight ratio of the disintegrating agents such ascrospovidone to that of agents such as calcium silicate can range from9:1 to 1:9.

The present invention contemplates the use of at least one lubricant toassist in the removal of tablets from the dies during tablet compressionand to reduce the friction of particles. Common hydrophobic lubricantssuitable in the present formulation are: magnesium stearate, sodiumstearyl fumarate, calcium stearate, sodium stearate, stearic acid, talc,hydrogenated vegetable oil, aluminum stearate, silica gel, such ascolloidal silicon dioxide, and mixtures thereof The presence of at leastone of the above mentioned lubricants is contemplated in the presentinvention. Preferred is a combination of magnesium stearate, NF andsodium stearyl fumarate, NF. Sodium stearyl fumarate is commonlyavailable under the tradename PRUV (Penwest Pharmaceuticals Co.,Patterson, N.Y.).

In addition to the above mentioned ingredients, other excipients can beadded to the present composition. In particular, coloring agents andflavoring agents can be added. Any coloring suitable for oral ingestion,including natural synthetic coloring such as F.D.& C. dyes, areappropriate in the present invention. A natural or an artificialsweetener can be employed to improve the taste of the tablet upondisintegration, such as aspartame, sucralose, acesulfame potassium,sodium cyclamate, saccharin and the like. In some embodiments, thesweetener is aspartame. In addition, natural and artificial flavoringscan be added. The citrus flavorings, including but not limited toorange, tangerine, lemon, lime, lemon-lime, citrus, and the like, areparticularly suited to combat the bitter taste of mirtazapine. In someembodiments, orange flavor is preferred. In some embodiments, strawberryflavor is preferred.

The pharmaceutical dosage forms of the present invention are useful inthe therapeutic treatment for patients suffering from DSM-IV diagnosabledisorders such as schizophrenia, Alzheimer's Disease, autism,depression, benign forgetfulness, childhood learning disorders, closehead injury, and attention deficit disorder. See U.S. Pat. No.6,228,875. In addition, the mirtazapine of the present invention can beused in treating movement disorders such as Parkinsonian tremors, rubraltremors, post-traumatic tremors, drug-induced tremors (e.g. induced bylithium or other drug agents), cerebellar tremors associated withlesions of the cerebellum or cerebellar outflow pathway, Tourette'ssyndrome tremors and other peripheral neuropathy-associated tremors,akathisias, asterixis, athetosis, choreaathetosis, tics,chorea/choreaform movements, dystonias, spasticity, restless legssyndrome, hyperkinetic movement disorders, hemiballismus, myoclonus,tardive dyskinesia and other types of dyskinesia, and sleep apneadisorders. See U.S. Pat. Nos. 6,281,207 and 6,303,595.

In addition, the mirtazapine dosage form can be used to treat othermental disorders and diseases currently being treated byantidepressants, such as, but not limited to, selective serotoninreuptake inhibitors (SSRIs) such as depression (including majordepression (single episode, recurrent, melancholic), atypical,dysthymia, subsyndromal, agitated, retarded, co-morbid with cancer,diabetes, or post-myocardial infarction, involutional, bipolar disorder,psychotic depression, endogenous, and reactive, obsessive-compulsivedisorder, bulimia. In addition, the formulations can be used to treatpeople suffering from pain (given alone or in combination with otherpain relievers), obsessive-compulsive personality disorder,post-traumatic stress disorder, hypertension, atherosclerosis, anxiety,anorexia nervosa, panic, social phobia, stuttering, sleep disorder,weight loss, agoraphobia, improving memory, amnesia, smoking cessation,nicotine withdrawal syndrome symptoms, disturbance of mood and/orappetite associated with pre-menstrual syndrome, depressed mood and/orcarbohydrate craving associated with pre-menstrual syndrome, disturbanceof mood, disturbance of appetite or disturbances which contribute torecidivism associated with nicotine withdrawal, circadian rhythmdisorder, borderline personality disorder, hypochondriasis,pre-menstrual syndrome (PMS), late luteal phase dysphoric disorder,pre-menstrual dysphoric disorder, trichotillomania, symptoms followingdiscontinuation of other antidepressants, aggressive/intermittentexplosive disorder, compulsive gambling, compulsive spending, compulsivesex, psychoactive substance abuse disorder, sexual disorder,schizophrenia, premature ejaculation, or psychiatric symptoms such asstress, worry, anger, rejection sensitivity, and lack of mental orphysical energy. See e.g., U.S. Pat. No. 6,150,353.

In some embodiments, the invention provides a process for preparing apharmaceutical tablet, the process comprising:

In some embodiments, the invention provides a process of making anon-effervescent, solid dosage form adapted for oral administrationwhich comprises:

a) mixing about 1 to about 60% by weight of mirtazapine;

about 1 to about 95% by weight of a hydrophilic component selected fromthe group consisting of a water-soluble component, a water-insolublecomponent, or combinations thereof, wherein the water-soluble componentis selected from the group consisting of cellulose derivatives, polyol,a component having a —CHOH group, water-soluble carbohydrate,hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, wherein the water-soluble carbohydrateis selected from the group consisting of mannitol, xylitol, sorbitol,malitol, lacitol, erytritol, xylose, arabinose, pentose, galactose,dextrose, inositol, sucrose, trehalose, and combinations thereof, acomponent having a —CHCOOH group, tartaric acid, citric acid, malicacid, succinic acid, sodium and potassium salts thereof, andcombinations thereof, and wherein the water-insoluble component isselected from the group consisting of microcrystalline cellulose,crospovidone, croscarmelose sodium, sodium starch glycolate, AMBERLITE,calcium silicate, calcium trisilicate, magnesium silicate, magnesiumtrisilicate, modified starches, and combinations thereof; and

up to about 5% by weight of at least one lubricant selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, talc, hydrogenated vegetableoil, aluminum stearate, silica gel, colloidal silicon dioxide, andcombinations thereof in an agitator to form a mixture;

b) followed by directly compressing the mixture to form a pharmaceuticaltablet,

wherein said tablet does not rely upon effervescence for disintegrationof said tablet, wherein dissolution of said dosage form in a medium of900 mL of 0.1 N HCl with a paddle speed of 50 rpm is greater than about75% at five minutes, and wherein the water-soluble and water-insolublecomponent are provided in a weight ratio from about 20:80 to about 95:5.In some embodiments, the dissolution of the dosage form in a medium of900 mL of 0.01 N HCl with a paddle speed of 50 rpm is greater than about95% at five minutes.

In some embodiments, the process further comprises mixing, about 1 toabout 50% of a first hydrophilic component selected from a groupconsisting of cellulose derivatives, hydrophilic polymers, polyvinylpyrrolidone, and combinations thereof. In some embodiments, the firsthydrophilic component is selected from the group consisting ofmicrocrystalline cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and combinationsthereof.

The non-effervescent, solid dosage forms formed from the present processhave a hardness of from about 0.1 to about 5 kp. In some embodiments,the hardness of the dosage forms can be 0.1 to about 3 kp. In someembodiments, the hardness of the dosage forms is greater than about 1.0kp after exposure for 24 hours at 25° C. and 60% relative humidity, andis greater than about 0.8 kp after exposure for 60 minutes at 40° C. and75% relative humidity.

When the solid dosage forms of the invention such as the tablets comeoff a tablet press, they are kept under low humidity conditions by useof, e.g., desiccated bags to control the moisture around the tablets.The tablets stored under desiccated conditions are then packaged intoblister packs under ambient controlled conditions at temperatures ofabout 25° C. and relative humidity ranging from about 35% to about 60%relative humidity, which results in a decrease in hardness of the tabletranging from about 0.1 to about 0.5 kp. While not wishing to be bound byany specific theory, it is believed that because a low amount of air istrapped inside a blister pack and around a packaged tablet, the relativehumidity of the atmosphere around a tablet inside a blister pack is low.Moreover, the packaging materials used for preparing the blister packsuch as aluminum are impermeable to moisture and maintain the conditionsof low humidity around the solid dosage forms for long periods of time.

When a user opens the package containing the solid dosage form toconsume the dosage form, then the dosage form is exposed to conditionssuch as about 25° C. and about 60% relative humidity, or about 40° C.and about 75% relative humidity, or about 25° C. and about 35% relativehumidity, or other ambient atmosphere, for periods of time whereby thehardness of the solid dosage form decreases. However, the formulation ofthe dosage form is such that even after exposure to conditions such asabout 25° C. and about 60% relative humidity for about 24 hours, orabout 40° C. and about 75% relative humidity for about 15 min, or about25° C. and about 35% relative humidity for about 24 hours, or about 25°C. and about 35% relative humidity for about 6 hours, or about 25° C.and about 35% relative humidity for about 1 hr, the hardness of theexposed dosage form is at least about 50% of the hardness of the dosageform when packed inside a package. This physical property of theformulations of the invention whereby the dosage form retains itshardness for a period of time after its removal from a package isadvantageous to users as patients do not have to consume the dosage formas soon as they open a package. In some embodiments, the package can beprepared under conditions including, but not limited to low humidity,controlled temperature, low oxygen, inert atmosphere, under nitrogen, invacuum, and combinations thereof.

In some embodiments, the invention provides, a non-effervescent, soliddosage form, wherein the dosage form having a first hardness being thedosage form inside a closed space, wherein the dosage form having asecond hardness being the dosage form exposed to about 25° C. and about60% relative humidity for about 24 hours, and wherein the secondhardness is at least about 50% of the first hardness. In someembodiments, the invention provides a non-effervescent, solid dosageform, wherein the dosage form having a first hardness being the dosageform inside a closed space, wherein the dosage form having a secondhardness being the dosage form exposed to about 40° C. and about 75%relative humidity for about 15 minutes, and wherein the second hardnessis at least about 50% of the first hardness.

The disintegrating tablets must be made under generally anhydrousconditions. To assist in the cohesion of dry ingredient, it is helpfulto include a hydrophilic component, which includes water-soluble andwater-insoluble components such as microcrystalline cellulose,hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose,and polyvinyl pyrrolidone. In some embodiments, the hydrophiliccomponent is microcrystalline cellulose, in particular, microcrystallinecellulose NF available under the trade name AVICEL PH 101 (FMCBioPolymer, Philadelphia, Pa.).

Some embodiments of the present invention are shown in Table 1.

TABLE 1 Mirtazapine Formulations Preferred More Most Ingredient % (mg)Preferred/mg Preferred/mg Mirtazapine 6.0 1 to 60 1 to 30 1 to 10Tartaric Acid 6.0 0 to 20 0 to 15 0 to 10 Microcrystalline 6.0 1 to 80 1to 50 1 to 10 Cellulose Citric Acid 8.4 0 to 20 0 to 15 0 to 10Aspartame 4.0 0.1 to 10 1 to 8 1 to 5 Orange Flavor 0.6 0 to 2.4 0 to1.2 0 to 0.6 Mannitol 43.6 0 to 80 0 to 60 0 to 50 Crospovidone 24.0 3to 50 5 to 40 10 to 30 Magnesium 0.6 0 to 5 0 to 3 0 to 1 StearateSodium Stearyl 0.8 0 to 5 0 to 3 0 to 1 Fumarate

A compressed tablet contemplated in the present invention has a hardnessof from about 0.1 to about 5 kiloponds (kp). In some embodiments, thehardness of the tablets ranges from about 0.1 kp to about 3 kp. In someembodiments, the hardness of the tablet is about 2 kp.

FIG. 1 depicts a flow chart of a manufacturing process which can be usedto form pharmaceutical tablets of the pharmaceutical composition of thepresent invention. Tartaric acid and microcrystalline cellulose aremixed in an agitator; citric acid, aspartame, orange flavoring,mirtazapine and mannitol are subsequently added and mixed to form amixture; crospovidone is then transferred to the agitator and mixed inwith the mixture followed by subsequent additions of sodium stearylfumarate and magnesium stearate; the composition is mixed and theresultant mixture is compressed to form mirtazapine pharmaceuticaltablets.

FIG. 2 depicts a flow chart of a dry mixing process to preparemirtazapine orally disintegrating tablets. Mannitol and xylitol aremixed and passed through a screen, and then mixed in a tumble blender,e.g., GEMCO 20 cubic feet (General Machine Company of New Jersey Inc.,Middlesex, N.J.). Mirtazapine and microcrystalline cellulose aresubsequently added to the tumble blender and mixed. Crospovidone andpolyvinyl pyrrolidone are added to the mixture. Strawberry flavor,aspartame and colloidal silicon dioxide are passed through a screen andthen added to the tumble blender and mixed with the above mixture, thenpassed through a screen and then again transferred to a tumble blender.Sodium stearyl fumarate and magnesium stearate are passed through ascreen, e.g. Russell Finex #30 (Russel Finex Inc., Pineville, N.C.), andadded to the tumble blender, mixed and then the blend is compressed intotablets using a tablet press.

The disclosed mirtazapine dosage forms can be prepared as a solid oraldosage forms, preferably as orally disintegrating tablets, for medicaladministration. The preferred method of administration is in the form ofa non-effervescent, orally disintegrating tablet compressed from amixture of the dry ingredients. In some embodiments, mirtazapine is inthe form of uncoated mirtazapine particles. The net weight of acompressed tablet comprising the mirtazapine dosage form of the presentinvention is from about 50 mg to about 1000 mg. Preferably, themirtazapine dosage form would be made commercially available in twostrengths, one about 250 mg and the other about 500 mg, each containingproportional doses of mirtazapine.

It has been unexpectedly found that mirtazapine tablets formed from thepresent pharmaceutical dosage form are physically stable at humidconditions although they have similar dissolution profiles to that ofreference mirtazapine effervescent tablets.

Moreover, the mirtazapine tablets of the present invention are easier topackage because they are more physically stable, less sensitive tomoisture and are thus less fragile than reference mirtazapine tablets.

While not wishing to be bound by a specific theory, it is believed thatupon oral administration to a patient, the dosage forms of the inventionundergo disintegration to form granules or aggregates or fine particles,and subsequently most of the mirtazapine is released into solution.

The following examples of processing conditions and parameters are givenfor the purpose of illustrating the present invention and shall not beconstrued as being limitations on the scope or spirit of the invention.

Examples Example 1

FIG. 1 is a flow chart describing the process for making the mirtazapineformula of the present invention. Microcrystalline cellulose andtartaric acid are combined in a 20 cubic foot GEMCO blender (GeneralMachine Company of New Jersey Inc., Middlesex, N.J.) for seven minuteswith the agitator off. The mixture is then milled, e.g., through aFITZMILL (Fitzpatrick, South Plainfield, N.J.) fitted with a 1522-033screen and a hammer forward. The mixture is then combined with citricacid, aspartame, orange flavor, mirtazapine, and mannitol and mixedagain in the GEMCO blender (General Machine Company of New Jersey Inc.,Middlesex, N.J.) with the agitator off. After 15 minutes, crospovidoneis added and the mixture is blended for another 15 minutes. The mixtureis then screened through #20 mesh and mixed again for 18 minutes. Sodiumstearyl fumarate is then added and the mixture is mixed for seven moreminutes. At which time, magnesium stearate, which has been passedthrough a #30 mesh screen, is added, and the mixing continues for afinal seven minutes. The mixture is then compressed into tablets on atablet press, e.g., KIKUSUI (Kikusui Tablet Press, Toms River, N.J.)using 13/32 inch flat-face bevel edge (FFBE) tooling for forming 15 mgmirtazapine orally disintegrating tablets, and 16/32 inch FFBE toolingfor forming 30 mg mirtazapine orally disintegrating tablets.

Example 2

The procedure of Example 1 was used to make the following 15 mgmirtazapine orally disintegrating pharmaceutical tablet:

TABLE 2 15 mg mirtazapine orally disintegrating tablet Milligrams/Ingredient Tablet % Mirtazapine 15 mg 6.0 Tartaric Acid 15 mg 6.0Microcrystalline Cellulose 15 mg 6.0 Citric Acid 21 mg 8.4 Aspartame 10mg 4.0 Orange Flavor 1.5 mg 0.6 Mannitol 109 mg 43.6 Crospovidone 60 mg24.0 Magnesium Stearate 1.5 mg 0.6 Sodium Stearyl Fumarate 2 mg 0.8 NetTablet weight 250 mg 100

Example 3

The procedure of Example 1 was also used to make the following 30 mgmirtazapine orally disintegrating pharmaceutical tablet:

TABLE 3 30 mg mirtazapine orally disintegrating tablet IngredientMilligrams/Tablet Mirtazapine 30 mg Tartaric Acid 30 mg MicrocrystallineCellulose 30 mg Citric Acid 42 mg Aspartame 20 mg Orange Flavor 3 mgMannitol 218 mg Crospovidone 120 mg Magnesium Stearate 3 mg SodiumStearyl Fumarate 4 mg Net Tablet weight 500 mg

Example 4

Table 4 depicts the comparative hardness (kp) for mirtazapine tabletsfor the 15 and 30 mg dosage forms tablets of Examples 2 and 3. The 15 mgand 30 mg tablets were determined to have a hardness from about 2.6 toabout 1.8 and from 2.7 kp to about 1.7 kp, respectively, at 25° C. and60% relative humidity (RH) when the tablets were exposed to theenvironment for up to 24 hours. Table 4 shows that at control roomtemperature, the hardness of the reference tablets decreased rapidlyover a period of time (i.e. the tablet breaks down and gets mushy).

TABLE 4 Comparative Hardness (Kp) data for Mirtazapine Tablets, 15 and30 mg Barr vs. Reference at 25° C./60% RH 15 mg 30 mg Time (Example 2),Reference 1, (Example 3), Reference 2, (Hours) kp kp kp kp 0 2.6 1.8 2.71.6 2 1.2 0.6 1.2 0.5 6 1.2 0.3 1.2 0.3 24 1.2 0.3 1.2 Powder 48 1.8 0.51.7 Powder

Table 5 shows that the hardness of the 15 mg and 30 mg dosage forms at40° C. and 75% RH ranged from about 2.8 kp to about 0.8 kp and fromabout 2.7 kp to about 1.1 kp, respectively, when the tablets wereexposed to the environment for up to one hour. Table 5 demonstrates thatthe physical integrity of the 30 mg mirtazapine tablet of the presentinvention is maintained under harsher conditions and is thus notspoiled. This physical property of the tablet is advantageous to usersof the tablet in hot and humid climates.

TABLE 5 Comparative Hardness (Kp) data for 15 mg and 30 mg MirtazapineTablets vs. Reference at 40° C./75% RH Time Barr Reference BarrReference (Hours) (15 mg), kp (15 mg), kp (30 mg), kp (30 mg), kp 0 2.81.9 2.7 1.9 0.25 1.5 0.6 2.0 0.5 0.5 1.5 0.4 1.4 0.4 0.75 0.9 0.4 1.10.4 1.0 0.8 0.4 1.1 0.4

Table 6 depicts the dissolution profile for the 15 mg dosage form, whichwas obtained in a dissolution medium of 900 mL of 0.01 N HCl with apaddle speed of 50 rpm. The table shows that about 100% of the 15 mgdosage form dissolves in five minutes.

TABLE 6 Comparative Dissolution Profile for 15 mg Mirtazapine OrallyDisintegrating Tablets Dissolution Medium: 0.01 N HCl 900 mL, 50 rpm,Paddle (Percent Dissolved) 15 mg Tablet Time Reference 1 (Example 2)(mins) 0010300046 202411001R 0 0 0 5 97 101 10 103 101 20 103 101 30 103101 45 103 101 60 103 101

Table 7 depicts the dissolution profile for a 30 mg dosage form of thepresent invention which was obtained in a dissolution medium of 900 mLof 0.01 N HCl with a paddle speed of 50 rpm. The table shows that about99% of the 30 mg dosage form dissolves in five minutes.

TABLE 7 Comparative Dissolution Profile for Mirtazapine OrallyDisintegrating Tablets 30 mg Dissolution Medium: 0.01 N HCl 900 mL, 50rpm, Paddle Dissolution Medium: 0.01 N HCl 900 mL, 50 rpm, Paddle(Percent Dissolved) 30 mg Tablet Time Reference 1 (Example 3) (mins)0010300046 202411001R 0 0 0 5 90 99 10 101 99 20 102 99 30 102 99 45 10299

Example 5

Table 8 shows 15 mg, 30 mg and 45 mg mirtazapine orally disintegratingtablet formulations prepared by the process shown in FIG. 2.

TABLE 8 Mirtazapine orally disintegrating tablets 15 mg 30 mg 45 mgTablet Tablet Tablet # INGREDIENT (mg) (mg) (mg) % 1 Mirtazapine 15.0030.00 45.00 9.375 2 Microcrystalline cellulose, 10.00 20.00 30.00 6.25NF (AVICEL PH101) 3 N-C NATURAL & 1.000 2.000 3.000 0.625 ARTIFICIALORANGE FLAVOR (POWDER) 4 Crospovidone, NF 42.00 84.00 126.0 26.25(POLYPLASDONE XL) 5 Mannitol, USP (PARTECK 76.30 152.6 228.9 47.68 M200)6 Colloidal Silicon Dioxide, 1.700 3.400 5.100 1.06 NF (CAB-O-SIL) 7Magnesium stearate, NF 1.500 3.000 4.500 0.937 8 Sodium stearylfumarate, NF 1.500 3.000 4.500 0.937 9 Xylitol (XYLISORB 300) 5.00010.00 15.00 3.125 10 Aspartame, USP (NUTRA 6.000 12.00 18.00 3.75 SWEETpowder) Total 160.0 320 480

Table 9 provides the disintegration time, friability and tablet hardness(kp) for the 15 mg, 30 mg and 45 mg formulations shown in Table 8.Friability, which is a measure of the crumbliness of the tablet is alsoprovided. As seen in Table 8, friability of the tablets at a hardnesslesser than about 1.5 kp is more than 2%.

TABLE 9 Disintegration time and friability Tablet HardnessDisintegration time (sec) Friability (%) (kp) 15 mg 30 mg 45 mg 15 mg 30mg 45 mg 0.5 3.3 5.2 6.33 100 100 100 1 4 5 6.4 100 100 100 1.5 4.7 6.76.7 0.1 60.6 100 2 5.7 6.3 5.7 <0.1 0.7 48 2.5 7.7 7.3 7 <0.1 0.7 18 3 —7.33 8 <0.1 0.1 2

Tables 10, 11 and 12 provide the effect of temperature and moisture(also referred to as relative humidity or RH) on the hardness of the 15mg, 30 mg and 45 mg formulations provided in Table 8. The results inTables 10, 11 and 12 are graphically depicted in FIGS. 3, 4 and 5. Asseen in Table 10, the hardness of 15 mg tablets exposed to 22° C./35% RHfor 6 hr was about 64% of the hardness of the tablets exposed for 0 min,i.e., the hardness of the tablet after exposure to 22° C./35% RH for 6hr was more than 50% of the hardness of the tablet exposed for 0 min.Further, the hardness of the 15 mg tablet exposed to 40° C./75% RH for15 min was about 57% of the hardness after exposure for 0 min, i.e., thehardness of the tablet after exposure to 40° C./75% RH for 15 min wasmore than 50% of the hardness of the unexposed 15 mg tablet.

Table 11 shows that the hardness of the 30 mg after exposure to 22°C./35% RH for 6 hr, or to 40° C./75% RH for 15 min was more than 50% ofthe hardness of the 30 mg tablet exposed for 0 min to either condition.

Table 12 shows that the hardness of the 45 mg after exposure to 22°C./35% RH for 6 hr, or to 40° C./75% RH for 15 min was more than 50% ofthe hardness of the 45 mg tablet exposed for 0 min to either condition.

TABLE 10 Effect of temperature/moisture on hardness of the 15 mgformulation Hardness (kp) Time 15 mg Tablet 15 mg Tablet 15 mg Tablet(min) 40° C./75% RH 22° C./35% RH 60° C. 0 1.4 1.4 1.4 5 1.0 1.4 1.3 100.9 1.4 1.3 15 0.8 1.4 1.3 30 0.5 1.4 1.3 45 0.5 1.2 1.3 60 0.5 1.2 1.3120 0.2 1.1 1.4 180 <0.1 0.9 1.3 240 <0.1 0.9 1.4 360 <0.1 0.9 1.4

TABLE 11 Effect of temperature/moisture on hardness of the 30 mgformulation Hardness (kp) Time 30 mg Tablet 30 mg Tablet 30 mg Tablet(min) 40° C./75% RH 22° C./35% RH 60° C. 0 1.9 1.9 1.9 5 1.2 1.8 1.8 101.1 1.9 1.8 15 1.2 1.7 1.8 30 0.9 1.7 1.6 45 0.9 1.7 1.9 60 0.9 1.8 1.7120 0.5 1.8 1.4 180 0.3 1.9 1.3 240 0.3 1.9 1.2 360 0.2 1.8 1.2

TABLE 12 Effect of temperature/moisture on hardness of the 45 mgformulation Hardness (kp) Time 45 mg Tablet 45 mg Tablet 45 mg Tablet(min) 40° C./75% RH 22° C./35% RH 60° C. 0 1.9 1.9 1.9 5 1.6 1.9 1.9 101.2 1.9 1.9 15 1.4 1.8 1.9 30 1.2 1.8 1.9 45 0.9 1.9 1.7 60 0.8 1.9 1.7120 0.7 1.9 1.8 180 0.4 2.1 1.6 240 0.4 2.1 1.4 360 0.3 2.0 1.3

Example 8

Table 13 shows 15 mg, 30 mg and 45 mg mirtazapine orally disintegratingtablets containing calcium silicate, which were prepared by the processshown in FIG. 2.

TABLE 13 Mirtazapine orally disintegrating tablets containing calciumsilicate 15 mg 30 mg 45 mg INGREDIENT Tablet Tablet Tablet % 1Mirtazapine 15.00 30.00 45.00 9.375 2 Microcrystalline cellulose, 10.0020.00 30.00 6.25 NF (AVICEL PH101) 3 N-C NATURAL & 1.000 2.000 3.0000.625 ARTIFICIAL ORANGE FLAVOR (POWDER) 4 Crospovidone, NF 21.00 42.0063.00 13.125 (POLYPLASDONE XL) 5 Calcium Silicate (FM 1000) 21.00 42.0063.00 13.125 6 Mannitol, USP (PARTECK 76.30 152.6 228.9 47.6 M200) 7Colloidal Silicon Dioxide, 1.700 3.400 5.100 1.06 NF (CAB-O-SIL) 8Magnesium stearate, NF 1.500 3.000 4.500 0.937 9 Sodium stearylfumarate, NF 1.500 3.000 4.500 0.937 10 Xylitol (XYLISORB 300) 5.00010.00 15.00 3.125 11 Aspartame, USP (NUTRA 6.000 12.00 18.00 3.75 SWEETpowder) Total 160.0 320.0 480.0 100

Table 14 provides the relationship between hardness of the 15 mg tabletof Table 10 and the disintegration time (DT).

TABLE 14 Tablet disintegration time vs. hardness Tablet Hardness DTFriability (kp) (sec) (%) 0.5 3.6 100 1 3.3 100 1.5 4 5.3 2 3 0.1 2.54.8 <0.1 3 5.7 <0.1 4 6.3 <0.1 5 8.3 <0.1

One skilled in the art would understand that, despite the fulldescription provided herein, the present invention can be performedwithin a wide and equivalent range of conditions, formulations, andother parameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

1-41. (canceled)
 42. A method of treating neurological disorders anddiseases which comprises administering a non-effervescent, orallydisintegrating mirtazapine tablet comprising: i) about 0.5% to about 10%of mirtazapine; ii) about 35% to about 65% by weight of water-solublecarbohydrate selected from the group consisting of mannitol, xylitol,sorbitol, sucrose and combinations thereof; iii) about 15% to about 35%by weight of a disintegrating agent selected from the group consistingof crospovidone, croscarmelose sodium, sodium starch glycolate andcombinations thereof; iv) about 5% to about 15% by weight ofmicrocrystalline cellulose; v) about 0.5% to about 4% by weight of atleast one lubricant; vi) 0 to about 10% by weight of a salivating agent;vii) optionally a coloring agent; viii) optionally a flavoring agent;and ix) optionally a sweetener. 43-51. (canceled)
 52. The method ofclaim 42 wherein the tablet comprises 15 mg, 30 mg or 45 mg ofmirtazapine and exhibits a hardness of about 1.5 kp to about 3 kp, ahardness greater than 1.0 kp after exposure for 24 hours at 25° C. and60% relative humidity and greater than about 0.8 kp after exposure for60 minutes at 40° C. and 75% relative humidity.
 53. The method accordingto claim 42 wherein the tablet disintegrates in about 3 to about 8seconds.
 54. The method of claim 42 wherein the hardness of the tabletis about 2 kp to about 3 kp.
 55. The method of claim 42 wherein thetablet comprises: i) about 0.5% to about 10% by weight of mirtazapine;ii) about 35% to about 65% by weight of mannitol; iii) about 15% toabout 35% by weight of crospovidone; iv) about 5% to about 15% by weightof microcrystalline cellulose; v) about 0.5% to about 4% by weight of atleast one lubricant; vi) 0 to about 10% by weight of a salivating agent;vii) colloidal silicon dioxide; viii) optionally a coloring agent; xi)optionally a flavoring agent; and x) optionally a sweetener.
 56. Themethod of claim 55 wherein the tablet comprises 15 mg, 30 mg or 45 mg ofmirtazapine and exhibits a hardness of about 1.5 kp to about 3 kp, ahardness greater than 1.0 kp after exposure for 24 hours at 25° C. and60% relative humidity and greater than about 0.8 kp after exposure for60 minutes at 40° C. and 75% relative humidity.
 57. A method of treatingneurological disorders and diseases which comprises administering anon-effervescent, orally disintegrating mirtazapine tablet prepared by amethod consisting of: a) preparing a dry mixture consisting of: i) about0.5% to about 10% by weight of mirtazapine; ii) about 35% to about 65%by weight of water-soluble carbohydrate selected from the groupconsisting of mannitol, xylitol, sorbitol, sucrose and combinationsthereof; iii) about 15% to about 35% by weight of a disintegrating agentselected from the group consisting of crospovidone, croscarmelosesodium, sodium starch glycolate and combinations thereof; iv) about 5 toabout 15% by weight of microcrystalline cellulose; v) about 0.5% toabout 4% by weight of at least one lubricant; vi) 0 to about 10% byweight of a salivating agent; vii) optionally a coloring agent; viii)optionally a flavoring agent; and ix) optionally a sweetener; and b)compressing the dry mixture into 15 mg, 30 mg or 45 mg mirtazapinetablets.
 58. The method of claim 57 wherein the tablet exhibits ahardness of about 1.5 kp to about 3 kp, a hardness greater than 1.0 kpafter exposure for 24 hours at 25° C. and 60% relative humidity andgreater than about 0.8 kp after exposure for 60 minutes at 40° C. and75% relative humidity.
 59. The method according to claim 57 wherein thetablet disintegrates in about 3 to about 8 seconds.
 60. The method ofclaim 57 wherein the hardness of the tablet is about 2 kp to about 3 kp.61. The method of claim 57 wherein the orally disintegrating mirtazapinetablet is prepared by a method consisting of: a) preparing a dry mixtureconsisting of: i) about 0.5% to about 10% by weight of mirtazapine; ii)about 35% to about 65% by weight of mannitol; iii) about 15% to about35% by weight of crospovidone; iv) about 5 to about 15% by weight ofmicrocrystalline cellulose; v) about 0.5% to about 4% by weight of atleast one lubricant; vi) 0 to about 10% by weight of a salivating agent;vii) colloidal silicon dioxide; viii) optionally a coloring agent; xi)optionally a flavoring agent; and x) optionally a sweetener.